Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections

Abstract

Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap2 method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with Cryptococcus neoformans meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.

Mining for novel antibiotics in the age of antimicrobial resistance

“…On another note, high‐throughput screenings (HTSs) of chemical libraries have been shown to represent efficient approaches for the identification of synergistic combinations of antimicrobials (i.e. the combined efficacy of two antimicrobials is greater than the sum of their individual effects; Wambaugh et al ., 2020). Remarkably, given the low rates in the discovery of new antimicrobials nowadays, the synergistic combination therapy not only offers the possibility to revitalize the use of existing antibiotics, but also increases the activity spectrum of the treatment, minimizes host toxicity and reduces the occurrence of AMR as synergistic drugs generally act against different cellular targets (Tyers and Wright, 2019).…”

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

“…Chemical–genetic mapping of synergistic compound pairs has been explored in Saccharomyces cerevisiae , but pathogen-specific analyses have revealed that many compounds display species-specific chemical–genetic interactions 118 . A high-throughput approach has been developed to predict synergistic and antagonistic drug pairs using at least one known synergistic drug pair and chemical–genetic data sets 118 , 119 . This approach, termed the overlap 2 method, has been applied to both fungal and bacterial pathogens.…”

“…This approach, termed the overlap 2 method, has been applied to both fungal and bacterial pathogens. For example, the overlap 2 method was applied to a compound library enriched for FDA-approved compounds against C. neoformans 116 – 119 and successfully predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy. Indeed, the combination of these drugs displayed enhanced efficacy in a mouse model of cryptococcal meningitis 119 .…”

“…For example, the overlap 2 method was applied to a compound library enriched for FDA-approved compounds against C. neoformans 116 – 119 and successfully predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy. Indeed, the combination of these drugs displayed enhanced efficacy in a mouse model of cryptococcal meningitis 119 . Several β-lactam antibiotics were identified as antagonistic with fluconazole in C. neoformans , an important consideration given that susceptible patient populations often have comorbidities 119 .…”

Factoring in the Complexity of the Cystic Fibrosis Lung to Understand Aspergillus fumigatus and Pseudomonas aeruginosa Interactions

“…Therefore, if further research were to confirm that pathogen growth is enhanced in combined infection, combinatorial treatment with drugs that have a synergistic or dual effect would be indicated. In this respect, some new azoles have been described to have anti- P. aeruginosa activity [ 151 ] and some antibacterial drugs have direct antifungal activity [ 152 , 153 ] and/or synergise with common antifungals [ 154 , 155 , 156 , 157 ]. In contrast, if the major effect of the interaction were to trigger secretion of a toxic compound, a virulence blocker would be beneficial.…”